Adenosine acts as a neuromodulator to inhibit neuromal firing and the release of neurotransmitters, as an inhibitor of platelet aggregation, as a cardiac depressant, and as as a vasodilator, a vasoconstrictor, as in the renal afferent arterioles and in the skin, as an immunosuppressant, and in a variety of other systems. Most of the physiological effects of adenosine involve binding to discrete membrane-bound adenosine receptors of the A.sub.1 or A.sub.2 subtypes. The xanthine drugs caffeine and theophylline, and many synthetic analogs, act as competitive antagonists at adenosine receptors. cf. K. A. Jacobson, in Receptor Biochemistry and Methodology, Vol. 11, ed. D. M. F. Cooper and C. Londos, pp. 1-26, 988.
Xanthines are well known drugs which are used clinically as bronchodilators, cardiotonics, diuretics, and central nervous system stimulants. The available evidence indicates that the therapeutic actions of these drugs involves blockade or antagonism of adenosine receptors. However, many of the xanthines, such as theophylline (1,3-dimethylxanthine), have undesirable side effects, such as cardiac stimulation. Some of these side effects may be due to actions at sites other than those of adenosine receptors. However, it is also likely that some side effects are associated with blockade of the adenosine receptors themselves.
Irreversible ligands, i.e. ligands that form a stable covalent bond with a receptor, have been synthesized for a number of receptors, including opiate receptors (Rice et al, Science, 220: 314-316 (1983) and Portoghese et al, Ann. Rev. Pharmacol. Toxicol. 25: 193-223 (1985), PCP (Rice et al. FEBS Letters 181: 318-322, 1985), adrenergic receptors (Pitha et al., J. Med. Chem. 30: 612-615, 1987), and benzodiazepine receptors (Newman et al., J. Med. Chem. 30:1901 (1987). The utility of chemically irreversible ligands for characterizing receptors in membranes and in physiological systems, and in receptor identification, has been demonstrated. For adenosine receptors, only photoaffinty labels have been described (Stiles, Trends Pharmacol. Sci. 7:486-490, 1986; Stiles et al., Mol. Pharmacol. 32: 184, 1987).
Kjellin et al, U.S. Pat. No. 4,546,182, disclose 3,8-dialkylxanthines which are substituted at the 8-position by methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert- butyl, or cyclobutyl.
Brown et al, U.S. Pat. No. 4,299,832, disclose substituted theophylline compounds substituted at the 8-position by alkyl or 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl, or phenylalkyl of 7 to 10 carbon atoms, each of which may be unsubstituted or substituted by one or more hydroxy groups, alkoxy, or alkylthio groups of 1 to 4 carbon atoms, halogen atoms, cyano groups, nitro groups, carboxy groups, alkoxycarbonyl groups of 2 to 5 carbon atoms, amino groups, alkylamino groups of 1 to 4 carbon atoms, or dialkylamino groups of 2 to 8 carbon atoms.
Bergstrand et al, U.S. Pat. No. 4,233,303, disclose xanthine derivatives substituted at the 8-position by methyl or n-propyl.
Bristol, U.S. Pat. No. 4,452,788, discloses 8-phenylxanthines of the following formula: ##STR1##
wherein R and R.sub.1 may be the same or different and are hydrogen, alkyl of from one to six carbon atoms, (CH.sub.2).sub.2-4 -N(R.sub.3).sub.2 wherein R.sub.3 is alkyl of from one to six carbon atoms, Ph(CH.sub.2).sub.1-3, or CF.sub.3 (CH.sub.2).sub.1-4.
Philippossian et al, U.S. Pat. No. 4,469,698, disclose xanthines substituted in the 8-position by methyl or ethyl.
Snyder et al, U.S. Pat. No. 4,593,095, disclose 8-phenyl-xanthines which are adenosine receptor antagonists. These compounds are of the formula ##STR2##
wherein X is NH, O, or S;
R.sub.1 is allyl, lower alkyl or cycloalkyl, the lower alkyl or cycloalkyl being substituted with hydroxy, lower alkoxy, or cyano;
R.sub.2 is hydrogen, allyl, lower alkyl, or cycloalkyl;
R.sub.3 is NH.sub.2 or OH;
R.sub.4 is halogen, halo-lower alkyl, phenyl, amino, hydroxyl, carboxy, lower alkyl, cycloalkyl, lower alkoxy, cycloalkoxy, lower alkoxyamino, lower alkylamino or cycloalkylamino, optionally substituted with hydroxy, primary amino, secondary amino tertiary amino, or carboxy, provided that R.sub.3 and R.sub.4 are not both amino when R.sub.1 and R.sub.2 are both bethyl; and
R.sub.5, which may be the same or different, is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxyl, nitro, or amino; or
X, R.sub.1, R.sub.2, and R.sub.5 have the meaning stated above, R.sub.3 is hydrogen, and R.sub.4 is hydrogen or has the meaning given above, except that R.sub.1 is other than methyl or ethyl when R.sub.4 is hydrogen, halogen, C.sub.1 -C.sub.3 alkoxy, amino, or alkylamino and R.sub.5 is halogen or hydrogen.
Jacobson et al, U.S. Pat. No. 4,612,315, disclose functionalized congeners of 1,3-dialkylxanthine which are antagonists for A.sub.1 - and A.sub.2 - adenosine receptors.